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Regulatory Focus™ > News Articles > Three Years After Warnings, FDA Bans Last High-Dose Aceptaminophen Products

Three Years After Warnings, FDA Bans Last High-Dose Aceptaminophen Products

Posted 16 July 2014 | By Alexander Gaffney, RAC

Three Years After Warnings, FDA Bans Last High-Dose Aceptaminophen Products

All prescription drugs containing high doses of acetaminophen have officially been withdrawn from the market, the US Food and Drug Administration (FDA) indicated in a regulatory filing this morning.


In January 2011, FDA requested that manufacturers discontinue marketing high-dose versions of acetaminophen—defined as doses higher than 325 mg—due the drug causing severe liver failure in some patients.

"Overdose from prescription combination products containing acetaminophen account for nearly half of all cases of acetaminophen-related liver failure in the United States; many of which result in liver transplant or death," said Sandra Kweder, then in charge of FDA's Office of New Drugs, in a statement.

"The risk of liver injury primarily occurs when patients take multiple products containing acetaminophen at one time and exceed the current maximum dose of 4,000 milligrams within a 24-hour period," she added. By limiting the size of the dose, FDA officials said they hoped to cut down on the number of accidental overdoses.

In a Federal Register notice, FDA said manufacturers would have until January 2014 to stop marketing high-dose variants of the drug, after which time they would be subject to "action by FDA." The agency also proposed instituting a Boxed Warning on all acetaminophen prescription products to reflect the elevated risks of drug-induced liver injury (DILI).

Manufacturers Comply

Since that announcement, FDA has been pushing for 100% compliance with its request, but has fallen short.

In March 2014, FDA announced the withdrawal of 108 abbreviated new drug applications (ANDAs) for prescription pain medications containing more than 325 mg of acetaminophen. As Focus noted at the time, the majority of the withdrawn products were not for pure acetaminophen products, but rather for combinations of the drug and other painkillers, such as hydrocodone and codeine.

In a follow-up announcement later in March 2014, FDA indicated that another five ANDAs would be withdrawn, leaving just a small handful of products on the market:

Application No.Drug product(s)Applicant or holderReason
ANDA 040117Vicodin HP (Acetaminophen and Hydrocodone Bitartrate Tablets), 660 mg/10 mgAbbVie Inc.Submitted a voluntary request for withdrawal under § 314.150(c).
ANDA 088058Vicodin (Acetaminophen and Hydrocodone Bitartrate Tablets), 500 mg/5 mgAbbVie IncSubmitted a voluntary request for withdrawal under § 314.150(c).
ANDA 089736Vicodin ES (Acetaminophen and Hydrocodone Bitartrate Tablets), 750 mg/7.5 mgAbbVie IncSubmitted a voluntary request for withdrawal under § 314.150(c).
ANDA 089166SYNALGOS-DC-A (Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Capsules), 356.4 mg/30 mg/16 mgLeitner PharmaceuticalsDid not submit a voluntary request for withdrawal.
ANDA 040366Acetaminophen and Hydrocodone Bitartrate Oral Solution, 500 mg/15 mL; 7.5 mg/15 mLNesher PharmaceuticalsSubmitted a voluntary request for withdrawal under § 314.150(c).
ANDA 040637Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Tablets, 712.8 mg/60 mg/32 mgWest-Ward Pharmaceutical Corp.Submitted a voluntary request for withdrawal, but failed to cite the appropriate regulatory provision.

Now FDA has announced that it has secured full compliance with its 2011 request—by force.

As FDA explains in a 16 July 2014 Federal Register announcement, four companies had submitted improper requests to remove the drug from the market. AbbVie, Nesher and West-Ward Pharmaceutical Corp. had all submitted requests under 314.150(c), instead of 314.150(d) of Title 21 of the Code of Federal Regulations.

150(c) allows a company to withdraw approval of an application based on a finding that the product is no longer marketed. 150(d), however, reflects a finding that the product is no longer safe, and that its problems are "sufficiently serious that the drug should be removed from the market."

As FDA explains in its notice: "With respect to the requests for withdrawal of approval submitted under § 314.150(c), the Agency notes that because FDA has made a determination under § 314.150(a) that approval of these applications should be withdrawn for reasons of safety, application holders may not withdraw their applications under § 314.150(c). The text of § 314.150(c) expressly precludes withdrawal of an application under the subsection if FDA has made a safety determination under § 314.150(a)."

Since the companies failed to respond to FDA's requests to remove the products under 314.150(d), FDA said it went forth with removal proceedings under 314.150(a) and (b), which allow it to remove a product from the market under its own regulatory authority.

While the regulations provide for a hearing on the withdrawal of the medicines, FDA said the companies had failed to respond to the notice, and therefore had waived their opportunity for a hearing on the matter.

"FDA is now withdrawing approval of their applications," the regulator wrote.

With their removal, FDA has now managed to remove all products containing more than 325 mg of acetaminophen from the market.

Federal Register Announcement


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